Discovery of Potent and Specific Fructose-1,6-Bisphosphatase Inhibitors and a Series of Orally-Bioavailable Phosphoramidase-Sensitive Prodrugs for the Treatment of Type 2 Diabetes
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- 作者：Qun Dang ; Srinivas Rao Kasibhatla ; K. Raja Reddy ; Tao Jiang ; M. Rami Reddy ; Scott C. Potter ; James M. Fujitaki ; Paul D. van Poelje ; Jingwei Huang ; William N. Lipscomb ; Mark D. Erion
- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：December 19, 2007
- 年：2007
- 卷：129
- 期：50
- 页码：15491 - 15502
- 全文大小：398K
- 年卷期：v.129,no.50(December 19, 2007)
- ISSN：1520-5126
文摘
Excessive glucose production by the liver coupled with decreased glucose uptake and metabolismby muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes.Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesispathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase).The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M.D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, wereport the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identifiedfollowing the combined discoveries of a low molecular weight inhibitor series with increased potency anda phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with theaid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase.High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with aphosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed tothe high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability(0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convertto the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oraladministration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significantblood glucose reduction.